This invention relates to a new method for inhibiting bone resorption that is mediated by the action of a class of cells known as osteoclasts, involving compounds that compete with osteoclasts for the osteoclast' site of activity.
Osteoclasts are multinucleated cells of up to 400 .mu.m in diameter that resorb mineralized tissue (chiefly, calcium carbonate and calcium phosphate) in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
In the method of the present invention, N-heterocyclicalkyl-substituted phenyl derivatives are administered in a pharmacologically effective amount that blocks osteoclasts from initiating bone resorption. These compounds have the general structural formula ##STR3## wherein
n is an integer of from 0 to 6;
Y is chosen from O, SO.sub.2, --CONH, --NHCO--, CH.sub.2 or ##STR4##
R.sup.1 is an unsubstituted or substituted saturated mono-or polycyclic hetero-cyclic ring system having 1, 2 or 3 heteroatoms where said heteroatoms are chosen from O, N or S and wherein said substituents are independently chosen from R.sup.2 ;
R.sup.2 is
C.sub.1-6 alkyl, PA1 aryl C.sub.0-6 alkyl, PA1 hydroxyC.sub.0-6 alkyl, PA1 C.sub.1-4 alkyloxyC.sub.0-6 alkyl, PA1 carboxyC.sub.0-6 alkyl, PA1 oxo, PA1 halogen, PA1 CF.sub.3, PA1 C.sub.0-4 alkylaminoC.sub.0-6 alkyl or PA1 C.sub.0-4 dialkylaminoC.sub.0-6 alkyl; PA1 hydrogen, PA1 C.sub.1-6 alkyl, PA1 hydroxyC.sub.0-4 alkyl PA1 C.sub.1-4 alkyloxyC.sub.0-4 alkyl PA1 carboxyC.sub.0-4 alkyl PA1 halogen or PA1 CF.sub.3 ; PA1 hydrogen, PA1 C.sub.1-6 alkyl, PA1 aryl C.sub.0-4 alkyl, PA1 C.sub.1-6 alkylcarbonyloxymethyl; and PA1 R.sup.5 is PA1 C.sub.1-6 alkyl, PA1 aryl C.sub.0-4 alkyl or PA1 heterocyclylC.sub.0-4 alkyl PA1 O, PA1 --NHCO--, PA1 --CONH-- or PA1 CH.sub.2 ; PA1 hydrogen, PA1 C.sub.1-6 alkyl, PA1 arylC.sub.0-4 alkyl, PA1 hydroxyC.sub.0-2 alkyl, PA1 C.sub.1-4 alkoxyC.sub.0-2 alkyl, PA1 carboxyC.sub.0-3 alkyl or PA1 oxo; PA1 H or PA1 C.sub.1-4 alkyl, PA1 O, --NHCO--, --CONH-- or CH.sub.2 ; PA1 C.sub.1-6 alkyl or PA1 aryl C.sub.0-4 alkyl,
R.sup.3 is
R.sup.4 is
and the pharmaceutically acceptable salts thereof.
A preferred group of compounds of the present invention are those defined for the general structural formula shown below wherein: ##STR5##
n is an integer from 0 to 6,
Y is chosen from
R.sup.1 is an unsubstituted or substituted 5 or 6-membered heterocyclic ring system having 1, 2 or 3 heteroatoms where said heteroatoms are independently chosen from N or O and wherein said substituents are C.sub.1-6 alkyl, aryl C.sub.1-3 alkyl, hydroxy, C.sub.1-4 alkoxy or oxo;
R.sup.2 and R.sup.3 are independently
R.sup.4 is
and the pharmaceutically acceptable salts thereof.
A more preferred group of compounds of the present invention are those adjusted for the general structural formula shown below wherein: ##STR6##
n is an integer of from 1 to 6;
Y is chosen from:
R.sup.1 is an unsubstituted or substituted 5 or 6-membered heterocyclic ring having 1 or 2 heteroatoms where said heteroatom is N and wherein said substituents are C.sub.1-3 alkyl, hydroxy or oxo; and
R.sup.2 is
and the pharmaceutically acceptable salts thereof.
The pharmacologic activity of these compounds is useful in the treatment of poultry and mammals, including man.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the U.S. In addition, there are 250,000 hip fractures per year attributed to osteoporosis, which are associated with a 12% mortality rate within the first two years and 30% of the patients require nursing home care after the fracture.
All the conditions listed above would benefit from treatment with agents which inhibit bone resorption.